Angiogenesis is essential for normal biological processes including reproduction, development and wound healing. Although angiogenesis is a highly regulated process in normal conditions, many diseases are caused by persistent disorders of angiogenesis. Theses diseases are called angiogenic diseases. That is, the disorders of angiogenesis can cause particular diseases directly, or exacerbate the existing diseases. For instance, the neovascularization in eye is the most common cause of blindness. In some existing diseases such as arthritis, new-developed capillaries invade the joint and destroy cartilage. In diabetes, new-developed capillaries invade vitreous, resulting in bleeding and blindness. Growth and metastasis of solid tumor depend on neovascularization which involves the degradation of the basement membrane of the starting blood vessel, the proliferation and migration of endothelial cells, and the development of new vessels (Folkman J. Angiogenesis in cancer, rheumatoid and other disease. Nature Med., 1995a, 1, 27-30) etc.
As a member of the family of platelet-derived growth factors, vascular endothelial growth factor (VEGF) is the most direct nitogen of vascular endothelial cells (Ferrara N., Molecular and biological properties of vascular endothelial growth factor. J. Mol. Med., 1999, 77:527-543). The activities of VEGF are mediated by binding to its receptors (VEGFR), and its biological effects are exhibited through endocellular signal transduction. The binding of VEGF to its receptor Flt-1 (fms-like tyrosine domain containing receptor) can result in endothelial cell migration, differentiation, and ultimately forming tubular structure (blood vessel rudiment). Flt-1 is an important target for inhibiting angiogenesis (Hanahan H., Signaling vascular morphogenesis and maintenance. Science, 1997, 277:48-50; Shinichi K. et al., Roles of two VEGF receptors, Flt-1 and KDR, in the VEGF effects in human vascular endothelial cells. Oncogene, 2000, 19: 2138-2146).
Some peptides acting as antagonists against VEGF binding to its receptor KDR are reported by Binetruy-Tournaire R. et al. in The EMBO Journal. 2000, 19(7): 1525-1533. It is said that they can inhibit the neovascularization induced by VEGF.
Due to the fact that the angiogenesis inhibitors clinically available are not satisfactory in terms of, among others, their severe system toxicity (Suramin) or weak activity of anti-angiogenesis (interferon, antiestrogen), therefore new angiogenesis inhibitors are needed.